Electrochemical measurements are widely used to determine the concentration of specific substances in fluids. These devices, referred to as ion-selective electrodes (ISEs), can be employed in a wide variety of potentiometric ion determinations, including, for example, the activity of fluoride ion in drinking water, the pH of process streams, and the determination of electrolytes in serum.
In the health care field, and particularly in the area of clinical diagnostics, ISEs are commonly used to measure the activity or concentration of various ions and metabolites present in blood plasma, serum and other biological fluids. For example, ISEs are typically used to determine Na.sup.+, Ca.sup.++, Mg.sup.++, K.sup.+, Cl.sup.-, Li.sup.+, pH, and carbon dioxide content in such fluids.
Conventional ion selective electrodes are typically composed of an ion selective membrane, an internal filling solution or electrolyte, and an internal reference electrode. Ion selective electrodes can be classified according to the nature of the membrane material, and include solid state membrane electrodes, glass membrane electrodes, liquid membrane electrodes having charged ion-selective agents, and neutral liquid membrane electrodes having membranes formed from an organic solution containing an electrically neutral, ion-selective agent such as an ionophore held in an inert polymer matrix. An external reference electrode used in conjunction with the ISE is typically a metal/metal halide electrode such as Ag/Ag/Cl.
An ion selective electrode exposed or subjected to a sample solution, such as a biological sample, and an external reference electrode comprise a potentiometric cell assembly. By selectively transferring the ion of interest from the sample solution to the membrane, a potential difference is generated. Under ideal selectivity conditions of the membrane for the anion of interest, the potential difference is a linear function of the logarithm of the activity ratio of the ion of interest in the two solutions contacting the membrane (Nernst equation). A semi-empirical extension of the Nernst Equation (Nikolskii Eisenmann equation) for EMF may be utilized for non-ideal conditions. By "EMF" is meant the electrical potential difference between the internal ion sensing and external reference electrode, the electrodes being electrolytically connected by means of the sample solution at zero or near zero current flow.
Conventional ISEs are typically bulky, expensive, difficult to clean and maintain, and tend to require an undesirably large volume of biological fluid. For these reasons, much attention has been directed towards developing more reliable ISEs of smaller size. These relatively small ISEs, referred to as ion-selective sensors or biosensors, can be inexpensively mass produced using techniques similar to these employed in the manufacture of electronic components, including for example, photolithography, screen printing, and ion-implantation.
Ion-selective sensors and biosensors can be manufactured at much lower production cost than conventional ISEs, making it economically feasible to offer a single-use or limited-use disposable device, thereby eliminating the difficulty of cleaning and maintaining conventional ISEs. The reduced size of ion-selective sensors further serves to reduce the required volume of patient sample. Generally, a sensor can be either a miniature version of a conventional electrode or a device constructed using one or more of the above mentioned techniques. Maximum accuracy of the analytical or diagnostic result is obtained when the sensor responds only to the concentration or activity of the component of interest and has a response independent of the presence of interfering ions and/or underlying membrane matrix effects. The desired selectivity is often achieved by an ion-selective membrane containing an ion selective agent such as an ionophore positioned over an electrical conductor.
Generally, ion-selective membranes are formed from a plasticized polymer matrix, such as polyvinyl chloride, which contains the ionophore selective for the ion of interest. For example, the ionophore valinomycin has been incorporated into a layer of membrane selective for potassium ions and trifluoroacetyl-p-butylbenzene or other trifluoroacetophenone derivatives have been used as ionophores selective for carbonate ions.
Many attempts have been made to determine chloride ion concentration in biological fluids. Both conventional electrodes and ion selective membrane electrodes as described above have been used for this purpose. These known electrodes are generally comprised of certain basic components including a solution of a polymer, such as polyvinylchloride (PVC) in a solvent such as cyclohexanone or tetrahydrofuran, an ionophore or ion selective component for selectively interacting with the chloride ion present in a sample solution, an optional plasticizing agent for rendering the membrane soft and pliable, and a reversible membrane conductor interface. Ionophores for chloride selective electrodes include various quaternary ammonium compounds, such as "Aliquat 336" (believed to be methyltricaprylcylammonium chloride) and tridodecylmethylammonium chloride (TDMAC) or quaternary phosphonium compounds. Typically, such ion selective components are chosen for their lipophilic properties and hence enhanced membrane life.
Ion selective membranes are routinely prepared by allowing the solvent present in the polymer to evaporate, thus providing for a membrane which can be molded from this mixture to a particular geometric design.
The composition of ion selective electrodes vary with respect to the amounts of polymer, plasticizer, and ionophore present in their formulations. In some electrodes, no plasticizer at all is present. U.S. Pat. No. 4,670,127 issued Jun. 2, 1987, to Ritter et al. discloses a chloride sensitive membrane having at least 50% electroactive component (ionophore) and no plasticizer at all. U.S. Pat. No. 4,349,426 issued Sep. 14, 1982 to Sugahara et al. discloses a membrane having a concentration of TDMAC from 10 to 20 percent by weight and that of PVC of from 20 to 40 percent by weight.
U.S. Pat. No. 3,772,175 issued Nov. 13, 1973, to Grubb discloses a univalent cation selective electrode prepared using a partially cured silicone rubber which is a dimethyl siloxane polymer filled with 44% by weight fumed silica filler.
A significant problem encountered in ion selective electrodes, such as chloride selective electrodes, is the presence of interfering substances present in biological samples. One such interfering substance is salicylate, which is known to interfere with chloride selective electrode determinations. Other interfering substances include bromide, ascorbate, and lipophilic anions such as rhodanide.
There is needed a simple chloride selective electrode with enhanced selectivity so as to reduce or minimize the effect of interfering substances such as other anions, lipophilic ions and other interfering substances present in biological substances.